GWAS of Type 2 Diabetes
Type 2 Diabetes Mellitus (T2DM) T2DM is a disease characterized by hyperglycemia (high blood sugar). This type of diabetes makes up for about 90% of diabetes cases. The main causes of type 2 diabetes include both environmental factors and a combination of different genetics, which were primarily unknown until this study. There has recently been an increase in the prevalence of this disease. This is most likely due to increased availability of food and decreased physical activity in many individuals. T2DM has been the subject of many studies because the heritability is so well known and researchers want further information on the exact genetic risk factors. Previous studies have shown many T2DM-linked chromosomal regions and loci, with the strongest known association being transcription factor TCF7L2. Study Design Part 1 This study was a two-part genome-wide association study. The purpose was to identify additional T2DM susceptible loci. The researchers obtained genotypes for 392,935 SNPs in 1,363 individuals, including individuals with T2DM and control individuals. The diabetic individuals were selected to have at least one affected relative and have ago onset under 45 years. Also, in order to reduce phenotypic heterogeneity, they studied individuals with a BMI of less than 30kg/m^2. The genotypes were obtained for each study subject using two methods: Illumina Infinium Human1 BeadArrays and Human Hap300 BeadArrays. The males and females were analyzed separately because of an unequal ratio in both cases and controls. Analysis Part 1 There were 28 autosomal SNPs from the Human1 chip and 43 autosomal SNPs from the Hap300 chip. This made for a total of 66 unique SNPs on 44 unique loci. 59 of these SNPs that showed significant association were prioritized for the second stage. This was done by looking at the differences between the observed and expected P-values. Study Design Part 2 The second part of the study involved obtaining genotypes from 2,617 T2DM cases and 2,894 control for 57 SNPs. In this part, there was no requirement of family history of T2DM or to be lean. Because there was a more relaxed criteria of individuals that participated in this study, the researchers used a logistic regression model to look at the effects of phenotypic variables, such as age, sex, and BMI. Analysis Part 2 This analysis confirmed the association of TCF7L2, which is on chromosome 10. They also identified 7 mroe SNPs representing 4 new T2DM loci. The most significant association was rs13266634, which is a non-synonymous SNP in SLC30A8 on chromosome 8. This gene encodes for a zinc transporter that is only found in secretory vesicles of beta-cells and is involved in final stages of insulin production. None of the results were changed by considering the phenotypic variables. Conclusion This study ended up finding 5 genetic variations that confer a risk of T2DM. The risk loci that were found involved genes primarily involved in pancreatic development and control of insulin secretion. The researchers believe that the identification of the variations at each of the loci could lead to possible treatments. They also concluded that the exclusion of obese individuals in the first part of the study was not great because it excludes any genetic variations that may only show themselves in obese patients. Resources Type 2 Diabetes Database: Type 2 Diabetes Mellitus- An introduction A genome-wide association study identifies novel risk loci for type 2 diabetes